Firsocostat (Gilead) is an acetyl-CoA carboxylase (ACC) allosteric inhibitor which binds to the biotin carboxylase domain of ACC with high potency and selectivity. Firsocostat inhibits both isoforms (ACC1 and ACC2) of ACC, which results in the reduction of the production of malonyl-CoA carboxylase, therefore reducing a key substrate for fatty acid synthesis. This also reduces the inhibitory effect of malonyl-CoA on the carnitine palmitoyltransferase 1 (CPT-1), which is the rate-limiting step in β-oxidation and leads to an increase in the breakdown of free fatty acids.
While 20mg firsocostat achieved a statistically significant reduction of 28.9% in magnetic resonance imaging proton density fat fraction (MRI-PDFF) compared to placebo in the Phase II monotherapy trial, data on anti-fibrotic measures have been less consistent. There was a degree of inconsistency with imaging of fibrosis, as FibroScan showed a numerical reduction in liver fat in the treatment group, whereas magnetic resonance elastography (MRE) stiffness showed a greater reduction in the placebo group. These variable results could be due to the difference in reliability of the imaging tools; while MRE measures stiffness of the entire liver, FibroScan has a more localized approach. Despite the convenience of using FibroScan, which can provide immediate results, MRE is arguably considered the more favorable measure in this case, as it is not affected by simple steatosis or ascites, and can acquire anatomical MRI.
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